2-Amino-4 H-pyrane

ABSTRACT

2-Amino-4 H-pyrane derivatives of the formula   WHEREIN R1 and R2 are the same or different and each is hydrogen or straight- or branched-chain alkyl; R3 is straight- or branched-chain alkyl, phenyl or -COOR&#39;&#39; wherein R&#39;&#39; is a straight, branched or cyclic saturated or unsaturated aliphatic hydrocarbon; R4 is straight, branched or cyclic alkyl or alkenyl, aryl unsubstituted or substituted by 1, 2 or 3 of the same or different substituents selected from the group consisting of alkyl, alkoxy, halogen, nitro, cyano, trifluoromethyl, carbalkoxy, and -SOn alkyl wherein n is 0, 1 or 2, or R4 is naphthyl, quinolyl, pyridyl, thenyl or furyl unsubstituted or substituted by alkyl, alkoxy or halogen; R5 is straight, branched or cyclic alkyl or -OR&#39;&#39;&#39;&#39; wherein R&#39;&#39;&#39;&#39; is a straight, branched or cyclic hydrocarbon or said hydrocarbon interrupted by 1 or 2 oxygen atoms; and R6 is hydrogen or alkyl; ARE USEFUL FOR THEIR STRONG CORONARY ACTION AND AS ANTIHYPERTENSIVE AGENTS.

United States Patent Meyer et al.

2-AMlNO-4 H-PYRANE Inventors: Horst Meyer; Friedrich Bossert, both of Wuppertal; Wult' Vater, Opladen; Kurt Stoepel, Wuppertal, all of Germany Assignee: Bayer Aktiengesellschaft, Germany Filed: July 2, 1973 Appl. No.: 375,809

Foreign Application Priority Data July l9, i972 Germany 2235406 US. Cl 260/34S.8; 260/287 R; 260/295 R; 260/3322 A; 260/465 D; 260/469; 260/470; 260/47l R; 260/476 R; 424/258; 424/263; 424/275; 424/283 Int. Cl C07d 7/14 Field of Search 260/3458 Primary Examiner-Norma S, Milestone ABSTRACT July 29, 1975 wherein R and R are the same or different and each is hydrogen or straightor branched-chain alkyl;

R is straightor branched-chain alkyl, phenyl or -COOR' wherein R is a straight, branched or cyclic saturated or unsaturated aliphatic hydrocarbon;

R is straight, branched or cyclic alkyl or alkenyl, aryl unsubstituted or substituted by l, 2 or 3 of the same or different substituents selected from the group consisting of alkyl, alkoxy, halogen. nitro, cyano, tfifluoromethyl, carbalkoxy, and SO, alkyl wherein n is 0, l or 2, or

R is naphthyl, quinolyl, pyridyl, thenyl or furyl unsubstituted or substituted by alkyl, alkoxy or halogen;

R is straight, branched or cyclic alkyl or -OR" wherein R" is a straight, branched or cyclic hydrocarbon or said hydrocarbon interrupted by l or 2 oxygen atoms; and

R is hydrogen or alkyl;

are useful for their strong coronary action and as antihypertensive agents.

16 Claims, No Drawings 2-AMINO-4 H-PYRANE to 7 carbon atoms or cycloalkenyl of 3 to 7 carbon atoms. aryl, especially phenyl. unsubstituted or substituted by 1,2 or 3 of the same or different substituents selected from the group consisting of ai kyl, especially lower alkyl, alkoxy. especially lower alkoxy, halogen. nitro, cyano. trif'luoromethyl. carbalkoxy. especially carbflower alkoxy), and SO,, alkyl. especially lower alkyl. wherein n is 0.

The present invention relates to 2-amino-4H-pyrane derivates. to processes for their production. to pharmaceutical compositions embodying said compounds as 5 the active ingredient and to their use as vasodilators and antihypertensive agents.

It has already been disclosed that the reaction of a,B-unsaturated carbonyl compounds with enamines I of leads to 2,3-dihydro-4 H-pyranes. for example: ll) R is naphthyl, quinolyl, pyridyl. thenyl or fury] unwas.

substituted or substituted by alkyl. especially lower alkyl. alkoxy, especially lower alkoxy. or halogen; R" is straight, branched or cyclic alkyl, especially straightor branched-chain lower alkyl, or cycloalkyl of 3 to 7 carbon atoms, or OR" wherein R" is a straight, branched or cyclic hydrocarbon, or said hydrocarbon interrupted by l or 2 oxygen atoms, especially straightor branched-chain lower alkyl, lower alkenyl. lower alkynyl, cycloalkyl of 3 to 7 carbon atoms. cycloalkenyl of 3 to 7 carbon atoms, or said lower alkyl, lower alkenyl. lower al- (compare l. W. Lewis. P. L. Myers. M. l. Readhead. J. Chem. Soc. C, 1970.771).

lnamines react similarly (J. Ficini. A. Krief. Tetrahedron Letters 1969. 1427).

Hitherto. nothing has been disclosed regarding a possible circulation-influencing effect of these 4 H- pyranes.

It has furthermore been disclosed that the reaction of 4-nitrobenzylidene-acetylacetone with potassium cyanide in an alkaline medium yields 3-acetyl-5-amino-2- methyl-4-(p-nitrophenyl) furane (see equation):

\ coCH3 ca ca -coca KCN 3 cn o 0 a 0 3 2N ac o=c-ca coca Ii (compare 1. P. Sword; J. Chem. Soc. C, I970. I916). kynyl. cycloalkyl of 3 to 7 carbon atoms. or cy- More particularly, the present invention is concerned cl lkcnyl 0f 3 t0 7 Carbon fltOmS inte up ed by l with 2-amino-4 H-pyrane derivatives of the formula: or 2 xygen 1mm; nd

R is hydrogen or alkyl. especially lower alkyl. The 2-amino-4 H-pyrane derivatives of the present invention are particularly useful because they exhibit a 0 5 H 3 R 0c R strong coronary action, particularly a vasodilating ac- 1 tion, as well as a good antihypertensive effect. The 6 compounds of the present invention may be produced R N 1 by reacting an a,B-unsaturated dicarbonyl compound of the formula wherein 3 R and R are the same or different and are each hyi =c u drogen or straight or branched-chain alkyl. espe- COR l f i h d h "K 1 H wherein R. R and R are as above defined.

' S Hug or mm. c a cspccm y a with an inamine of the formula lower alkyl. phenyl or COOR' wherein R is a I straight, branched or cyclic saturated or unsatu r-( R m rated aliphatic hydrocarbon. especially lower alkyl. R l0 er alkenyl. lou er alkynyl. cycloalkyl of 3 to 7 wherein R. R and R are as above defined except that carbon atoms or cycloalkenyl of 3 to 7 carbon R is not COOR' in an inert organic solvent at a tematoms; perature of from about 10 C to about 200 C. to pro- R is straight. branched or cyclic alkyl or all-zcnyl. csduce a compound wherein R is other than C()()R'.

pecially lower alkyl. lower alkenyl. cycloalkyl of 3 or b. with a cyanoacetic acid ester of the formula :t IV

wherein R is -COOR' wherein R is as above defined. in an inert organic solvent at a temperature of from about 10 C to 200 C. to produce a compound wherein R" is -COOR wherein R is as above defined. and recovering the compound produced.

The two forms (a) and (b) of the process according to the invention are referred to throughout this specification as Process Variants (a) and (b).

The compounds according to the invention. of the general formula I. are distinguished by a long-lasting strong vasodilating action. Hitherto. no pharmaceutical action of such 2-amino-4 H-pyrane derivatives has been disclosed. The compounds according to the invention represent new agents for the treatment of circulatory illnsesses and are hence an enrichment of pharmacy.

lf 2'-trifluoromethylbenzylideneacetoacetic ethyl ester and 1-N.N-diethylaminopropine are used as starting compounds. the course of the reaction can be represented by the following equation:

' '7 Process Variant (a):

If 3'-nitrobenzylideneacetoacetic acid methyl ester and cyanoacetic acid ethyl ester are used as starting compounds. the following equation applies:

Process Variant (b):

According to one embodiment of the present inven- I 55 tion R' and R are the same or different and each are alkyl of l to 4 carbon atoms:

R is straightor branched-chain alkyl of l to 4 carbon atoms. phenyl or --CO()R' wherein R is fill straightor branched-chain alkyl of l to 5 carbon atoms. straightor branched-chain alkenyl of 2 to 5 carbon atoms. straightor branched-chain alkynyl of 2 to 5 carbon atoms. cycloalkyl of3 to 5 car R is straightor branched-chain alkyl of l to b carbon atoms. cycloalltyl of 3 to 6 carbon atoms. phenyl unsubstituted or substituted or substituted by l bon atoms. or eycloalltenyl of 3 to 5 carbon atoms; 65

or 2 of the same or different substituents selected from the group consisting of alkyl of l to 4 carbon atoms. alkoxy of l to 4 carbon atoms. halogen (especially chloro or bromo). nitro. cyano. trifluoromethyl. carbalkoxy of l to 4 carbon atoms in the alkoxy moiety and SO,, alkyl wherein the alkyl moiety is of l to 4 carbon atoms and n is U or 2. or naphthyl, pyridyl. thenyl or furyl unsubstituted or substituted by alkyl of l to 4 carbon atoms. alkoxy of l to 4 carbon atoms or halogen;

R is straightor branched-chain alkyl of l to 4 carbon atoms or OR" wherein R" is straightor branehed-chain alkyl of l to 5 carbon atoms. straightor branched-chain alkenyl of 2 to 5 carbon atoms. straightor branched-chain alkynyl of 2 to 5 carbon atoms. cycloalkyl of 3 to 5 carbon atoms. cycloalkenyl of 3 to 5 carbon atoms. or straightor branched-chain alkyl of l to 5 carbon atoms or alkenyl of 2 to 5 carbon atoms interrupted by 1 oxygen atom; and

R is hydrogen or alkyl of l to 4 carbon atoms.

According to another embodiment of the present invention R and R are the same or different and each are hydrogen. methyl or ethyl;

" z sh R is methyl. ethyl. phenyl or COOR' wherein R is methyl. ethyl or allyl;

R is methyl. phenyl unsubstituted or substituted by nitro. cyano. trifluoromethyl. chloro. methyl. carbethoxy. l to 3 methoxy moieties. nitro and methoxy. nitro and trifluoromethy]. nitro and thiomethyl. or nitro and ehloro. or

R is naphthyl. pyridyl. quinolyl. furyl or thenyl;

R is OR" wherein R is methyl. ethyl. propyl. allyl or cyclohexyl'. and

R is methyl or ethyl.

According to another embodiment of the present invention R' and R are the same or different and each are hydrogen. methyl or ethyl;

R is methyl. carbomethoxy. or carbethoxy;

R is methyl. phenyl. unsubstituted or substituted by nitro. chloro. trifluoromethyl. methyl. methoxy. cyano. carbethoxy or nitro and chloro; or

R is naphthyl. furyl or thenyl',

R is metho\y, ethoxy. or propoxy; and

R is methyl.

The afimnsaturated dicarhonyl compounds of general formula [I are used as starting compounds in the process according to the invention are already known or can be manufactured according to known methods (Org. Reactions XV, 204 and thereafter (1967)).

Representative a,B-unsaturated dicarbonyl compounds include:

Benzylideneacetoacetic acid methyl ester, ethylideneacetoacetic acid methyl ester, isopropylideneacetoacetic acid methyl ester, 2'nitrobenzylideneacetoacetic acid methyl ester, 2'-nitrohenzylideneacctylacetone, benzylideneacetylacetone, 3'-nitrobenzylideneacetoacetic acid methyl ester, 3'-nitr0benzylideneacetoacetic acid propargyl ester, 3'-nitrobenzylideneacetoacetic acid allyl ester, 3'-nitrobenzylideneacetoacetic acid B-methoxyethyl ester, 3'-nitr0benzylideneacetoacetic acid B-ethoxycthyl ester, 3-nitrohenzylideneacetoacetic acid isopropyl ester, 3'-nitrobenzylideneacetylacetone, 4'-nitrohenzylideneacetylacetone, 4"nitrohenzylideneacetoacetic acid B-propoxyethyl ester, 4'-nitrobenzylideneacetoacetic acid n-propyl ester, 3'-nitro-6'-chlorobenzylideneacetoacetic acid methyl ester. '-cyanohenzylidencacctoacetic acid methyl ester, '-cyanohenzylideneacetoacetic acid methyl ester, I cyanobenzylideneacetoacetic acid ethyl ester,

'-cyanobenzylidenepropionylacetic acid ethyl ester, '-cyanobenzylideneacetoacetic acid methyl ester, '-nitro-4'-chlorobenzylideneacetylacetone, 3'-nitro-4'chlorohenzylideneacetoacetic acid t-butyl ester, 3'-nitro-4'-chlorobenzylideneacetoacetic acid methyl ester, 2' nitro-4-methoxybenzylideneacetoacetic methyl ester, 2-cyano4-methylhenzylideneacetoacetic acid ethyl ester, 2'-methylmercaptobenzylideneacetoacetic acid isopropyl ester, 2-sulphonylmethylbenzylideneacetoacetic acid ethyl ester,

acid

2-sulphonylhenzylidenemethylacetoacetic acid allyl ester, 4-sulphonylmethylhenzylideneacetoacetic acid ethyl ester.

( l'-naphthylidene)acetoacet1c acid methyl ester,

( l-naphthylidenel-acetoacetic acid ethyl ester.

l2'naphthylidene)-acetoacetic acid ethyl ester.

(2'-ethoxy-l"naphthylidenel-acetoacetic acid methyl ester.

(T-methoxy-l'-naphthylidenel-acetoacetic acid ethyl ester,

5' hromo( l'-naphthylidenel-acetoacetic acid methyl ester,

l2-quinolyll-methylidencacetoacetic acid methyl ester,

(4'-c uinolyl) methylidcneacetoacetic acid ethyl ester,

(8'-quinolyl)-methylidencacetoacetic acid ethyl ester,

oz-pyridylmethylideneacetoacetic acid methyl ester, a-pyridylmethylideneacetoacetic acid ethyl ester. a-pyridylmethylideneacetoacetic acid allyl ester. (r-pyridylmethylideneacetoacetic acid cyclohexyl ester, ,G-,)yridylmethylideneacetoacetic acid B-methoxyethyl ester, y-pyridylmethylideneacetoacetic acid methyl ester, 6-methyLa-pyridylmethylideneacetoacetic acid ethyl ester,

(Z'-thenyll-methylideneacetoacetic acid ethyl ester,

t2'-furyl)-methylideneacetoacetic acid allyl ester,

3'-nitrohenzylidenepropionylacetic acid ethyl ester,

a-pyridylmethylidenepropionylacetic acid ethyl ester,

a-pyridylmethylidenepropionylacetic acid methyl es ter,

a-pyridylmethylideneacetylacetone-Z'-, 3'- and 4'- methoxybenzylideneacetoacetic acid ethyl esters,

2-, 3'- and 4'-methoxybenzylideneacetylacetone,

2'-methoxybenzylideneacetoacetic acid allyl ester,

2'-methoxybenzylideneacetoacetic acid allyl ester,

2'-methoxybenzylideneacetoacetic acid propargyl ester,

2 methoxybenzylideneacetoacetic acid B-methoxyethyl ester,

2-is0propoxybenzylideneacetoacetic acid ethyl ester,

3'-butoxybenzylideneacetoacetic acid methyl ester,

.3, 3', 5-trimethoxybenzylideneacetoacetic acid allyl ester,

2'-methylhenzylidenepropionylacetic acid methyl ester,

2-. 3- and 4'-methylbenzylideneacetoacetic acid ethyl esters,

2-methylbenzylideneacetoacetic acid B-methoxyethyl ester,

2-methylbenzylideneacetoacetic acid B-propoxyethyl ester,

2-methylhenzylideneacetoacetone,

3,4'-dimeth0xy-5'-hromobenzylideneacetoacetic acid ethyl ester.

2'-, 3'- and 4-chloro/bromo/fluorobenzylideneacetoacetic acid ethyl esters,

2'-fluorobenzylideneacetoacetic acid methyl ester,

3 '-chlor0benzylideneacetylacetone,

3'-chlor0benzylidenepropionylacetic acid ethyl ester,

3'-chlorobenzylideneacetoacetic acid ethyl ester,

2'-chlorobenzylideneacetoacetic acid allyl ester,

2-, 3'- and 4'-triflu0romethylbenzylideneacetoacetic acid isopropyl ester,

3'-trifluoromethylbenzylideneacetoacetic acid methyl ester,

2'carboethoxybenzylideneacetoacetic acid ethyl ester,

3'-carboxymethylhenzylideneacetoacetic acid methyl ester and 4-carboxymethylbenzylideneacetoacetic acid allyl ester,

The inamines of formula Ill are used as starting compounds in Process Variant (a) according to the invention are already known or can be manufactured ac cording to known methods (H. G. Viehe, M. Reinstein, Ang, Chem. 76, 537 (1964)).

Representative inamines include:

l -Dimethylamino-Z-phenylacetylene, l-diethylamino-Z-phenylacctylene, l-dimethylamino-3 ,3-dimethylhutl -ine, l-diethylaminopropl -ine, l-dicthylaminohutl -ine and l-diethylaminohexl -ine.

7 8 The cyanoucetic acid esters of formula l'v used :is a, 1 i'n i i,i i o touliniethyl-tl2'-naphthyl)-4 starting materials in Process Variant (hi according to H pyranoi carlioxvlic acid isopropyl ester. the invention are already known llnglis. Org. Synth o, F-hietliylumi oitndi hyln-(4'-quinolyl)-4 Coll. Vol. l. 249 ll932l). Hpyrane i-caiboxylie acid ethyl ester.

Representative cyanoacetie acid esters incl e. n j'lig il' lunllnfl f iih.l h lnelhyl ld3 4 s-tfimfitlioxyplienyl l--l li p rune fi carboxylic acid allyl cyanoacctic acid ethyl ester. ester. cymoacetit; acid methyl ester. l'h eovn t'uuids of the present invention have dem cyanoacetie acid propyl ester. onstrated the follou lug pharmaeological activity in anicyanoacetic acid isopropyl ester. to ma! tests; cvanoacetic acid butyl ester. l. t'Jn parenteiai. oral and perlingual administration cyanoacetic acid allyl ester. the compounds of the present invention produce a dis- WH B Milk] pr p gy BSIEY 11ml duct and long-lasting dilation of the coronary vessels. eyanoacetic acid fi-metht'ixvethyl Cst r. this action on the coronary vessels is intensified by a l9 simultaneous lllll'llL lllsL effect of reducing the load on Generally all inert organic solvents can be used as i the heart The conniiounds influence or modify the solvent in the bove process. Such solvents include. flu heart metabolism in the sense of an energy saving. example. alcohols (such as methanol, ethanol and pro- 1T1 ompounds of the present invention lower the pan l). ethers {such as diozane and diethyl etherl n blood presure of norinotonic and hypertonic animals hydrocarlmns lsuch as cyclohexane. benzene. toluene and can thus be used as antihypertensive agents and xylene Preferably. according to Process variant 3. The excitability ofthe stimulus formation and exci- (a). lu n is d n according In Process variant lation conduction system within the heart is lowered so (b). ethanol is used. that an antifibrillation action demonstrable at thera- While the reaction temperatures can be varied over -m' Line gultge a substantial range (from about 10 C to about 2th) (f; 35 4 'th time h smooth ntugclg f the ve el i as indicated above. the preferred temperature range is gr atly redu d und r th notion of the COmpOUl'ldS 0f betvveen about Zll and about list! L. and especially the present invention this vascularspasmolytic action at about the boiling p int of SUIWHI- can take place in the entire vascular system or can Process Variant (bl is preferably carried ut in th manifest itself mote or less isolated in circumscribed presence of a basic condensation catalyst such as an or vascular regions (such as. for example. the central nerganie base; for example. piperidine. m5 o y In carrying out the process of the present invention The compounds of the present invention have the starting materials are preferably reacted in substanl l rt dciigng hi h if tially molar proporti ns. F themselves on the smooth muscle of the stomach. of Representative 2-aniino-4 H yranes according t the intestinal tra t. of the urogenital tract and of the rethe present invention include: 591mm.

a. 2-Amino-6-methyl4-i2'-ni1rophenylt l H-pyrane 6. the compounds of the present invention influence 3.5-dicarboxylic acid diethyl ester. the cholesterol level and lipid level of the blood. b. 2-Amino-6methyl-4% n mP ml 4 l l The compounds of the present invention may also be 3,5-dicarboxylic aciid 3ethyl ester S-methyl ester. formulated into pharmaceutical compositions. The C. 2-Amino-6-ethyl4-( -ni r ph vll-4 H-pyranepharn'iaceutieal compositions of the present invention 3ls-dlcilrl7'oxyllc acid y cstcrcontain a ninior or minor amount. c.g.. from 99.5 to d. Z-Amino oanethyl-llT-nitroh tll'T t. referably "t.- to Ilfifil. of the active agent as mcthoxyph nyll -py 'l i5dicarboxylic acid herein defined in combination with a pharmaceutical diethyl ester. carrier. he carrier comprising. one or more solid. semic. 'A 'fl flw l hyl- -(Z'trifluororni.:tliyl-4' solid or liquid diluent. fill r and formulation udjuvant nitrophenyl)-4 H-pyrane-3.i dicarboxyiic iltllt ."itvhit' non-torti hurt and pltaimaceuticallv acceptcthyl estenS-methyl ester. able Such pliariuriceutiiul compositions are preferably 2'. Z-Amino-ounethyll (3-nitro-h (W in dosage nit fortn' i e.. physically discrete units con methylmcrcaptophenyll-3.5-tlicarlioyxlic acid di training a predetermined amount of the drug corremethyl ester. spouding to a fraction or multiple of the dose which is g. I1-Amino-(i-incthyl4-lT-Cyanophenyll-l calculated to produce the desired therapeutic response. H-pyranc-3.5-dicarbotylic acid tally] ester-5 ethyl the dosage units can contain one. two. three. four or ester. more single doses or. alternatively. one half, third or h. 2-Aminoh-mcthylA-i V-nitrophenvlMl ll-pyranefourth of a f illt dose. A single dose preferably con- 3.5-dicarboxylic acid 3-ethyl esterfi cyelohet l es talus an anion n; to produce the desired therapcutit. effect upon adiriintstiation at one application of i. 2-DimethylaminoS-inclhyI-trcthyl-4t 3 'tarbe one r 111m e dosa "c units according to a predetermined thoxyphenyll-4 H-pyrane-5-carhoxylie acid ethyl H. d usually a Whole. half, third. or quarter ester. of the d. v dosage athriinistered once, twice. three or ls. lDiethylamino 3'Cll1)l -l'l1t?[l1\l -l lf.l:--t1,tltl tll i four tunes n tlav. tlther therapculie agents can also be H-pyrane-5-carhoxylic acid isopronvl ester, present.

I. lDiemethylaminolinethyl-li ethyhl ill Although the llUnLtgL and dosage regimen must in cyanophenylwl l'l-pyrain i'carb sylie acid clhyl t-aeii e be twu'tl'ully dLllLlHlLLl. utilizing sound profes- Uslcfiouai iudt'uuut and considering; the age. weight and m. DlCli'lyltllllllllhB-[llliillll ll lllfiillly ll l' tri li l lllll lll of tinrecipient. the route of administration fluoromethylphenyll 4- llpyrane fiturliosyhe acid and the nature and gravity of the illness. generally the y dosage for iuliliitinal administration will be from 0.25

mg to )litl mg. preferably l to till mp Inc prclcrretl oral administration i 5 mg to 45 prctcrnl'ily 5t mg U117 g. in each case. the dosage represents the amount of active ingredients to be administered. the daily dosage on iv. administration is preferably tttltl mgi'lqg to 10 mglkg. particularly (H32 to 5 mgiizg. and f r orai ad ministration is U i to 50 mgikg. particularly l to 3U mg /kg. In some instances a sufficient therapeutic flitt't can be obta ned at a lower dose while in others. a larger dose will he required.

Oral administration can be effected utili/ing sol d and liquid dosage unit Forms such as powders. tablets. d agecs. capsules. granulutcs. suspcnsionz-r. solutions and the like.

Powders are prepared by comnrinuting thc com pound to a suitahli; t'ine size and mixing with a similarly comminuted pharmaceutical carrier such as an edible carbohydrate as for example starch. lactose. sucrose. glucose or inannitoi. Swectening. flavoring. prcser w rive. dispersing and coloring agents can also be present.

Capsules are made by preparing a powder mixture as described Lll O'vLJ and tilling lorrned geiatin sheaths. {Eli dants and lubricants such as colloidal silica. talc. mag; nesium stearatc. calcium stearate or solid polyethylene glycol can be added to the DOV-Kit?! mixture before the filling operation. A disintegrating or soluhilii'ing agent such as agaragar. calcium carbonate or sodium carbon ate can also he added to ilnpro e the a ailability oi the medicament when the capsule is ingested.

Tablets are formulated. for examp c. by preparing a powder mixture. granulating or slugging. adding a in bricant and disintegrant and pressing the tubtetc. A powder mixture is prepared by mixing the compound. suitably comminuted. with a diluent or base as described above. and optionally with a binder such as carboxymethyl cellulose an alginatc. gclutin. or polyvinyl pyrrolidone. a solution retardant such a paraffin. a re sorption accelera or such as a quaternary salt andl'or an absorption agent such as beutonitc. kaolin or diealcium phosphate. The powder mixture can he granulated by wetting with a binder such as syrup. starch paste. acacia mucilage or solutions oi'ccllulosic or polymeric materials and forcing through a screen. As an alternative to granulating. the powder mixture can be run through the tablet machine and the rcsultin imperfectly formed slugs broken into granules. The granules can he luhri cared to prevent sticking to the tablctt'orniing dies hy means oi the addition of stcaric acid. a stcirutc salt. talc or mineral oil. The lubricated mixture is then compressed into tablets. The nicdicamcrits an also be combined with fret flowing. inert carricrs uni! compressed into tablets directly without going through the gt anuiat ing or slugging steps. A clear or opao uc protecthc coating consisting of a sealing (Jo-4; of shellac. 1i coating of sugar or polymeric material and a po ish coating; ot wax can he provided liycstul'is can hi. added to these coatings to distinguish ilit't'cient unit dosages.

Ural fluids such as solutions. sylups and elirtns can be prepared in dos: c unit form so that a giv n rptantit} contains a prct'leterinined amount oi the compound Syrups can he prepared by dissolving thc compound in a suitably Flavored atpicous sucrose solution Mhilc cli r irs are prepared through the use l .1 ru n-tr n alcoholic vehicle. Suspensions can he toi'muiatcd in dis persing the conipolui l in u lltili lt kit iclnclc, ioliiluliy crs and crnuisiticrs such as cthoi latcil l'nt HitLlt l lllctt hols and polyosycthy ltttc soi hitol estcrs. preservation.

till

flavor additives such as peppermint oil or saccharin. and thc like. can also be added.

\Jhere appropriate. dosage unit lormulations for oral administration can be mierocncapsulated. 'lhe formuiation can also be prepared to prolong or sustain the relea e as l'or example by coating or embedding particulatc material in polymers. was or the like Parenteral administration can be effected utilizing liquid dosage unit forms such as sterile solutions and suspensions intended for subcutaneous. intramuscular or intravenous injection. These are prepared by suspending or dissolving a measured amount of the compound in a nontoxic liquid vehicle suitable for injec tion such as an aqueous or oleaginous medium and steriliring the suspension or solution. Alternatively. a mcasured amount of the compound is placed in a vial and the vial and its contents are sterilized and sealed. An accompanying vial or vehicle can be provided for mix ing prior to adminstration. Non-toxic salts and salt solutions can be added to render the injection isotonic. Stabilizers. preservatives and emulsifiers can also be added.

Rectal ".ulministration can be effected utilizing sup ositories in which the compound is admixed with lowmelting water-soluble or insoluble solids such as polyethylene glycol. cocoa butter. higher esters as, for example. nyristyl palmitate. or mixtures thereof.

topical admistration can be effected utilizing solid dosage unit lorms such as powders or liquid or semiliqoid dosage unit forms such as solutions. suspensions. ointmcnts. pastes. creams and gels. The powders are formulated utilizing such carriers as talc. bentonitc. si lieic acid. polyarnide powder and the like. Liquid and semiliquid formulations can utilize such carriers. in addition to those described above. as polyethylene glycol. vegetable and mineral oils. alcohols such as isopropanol and the like. Other excipients such as emulsifiers. preservatives. colorants. perfumes and the like can also be present. Formulations can also be administered as an aerosol, utilizing the usual propellants such as the chlorofluorohydroearbons. Oral and intravenous compositions are preferred.

The coronary action of compounds representative of those of the present invention is set forth below in Table l;

Table l Distinctly discernible rise in 'thc oxygen saturation in the coronary lrcparntiuc Duration of l r runplc No intravenously) Action t tt i 9U mins 1 l 5 30 mins n it) 20 mins Table ll Lowering of blood Toxicity in pressure in high Compound of mice. mg/kg blood pressure rails. Prcpurntiw administered mg/kg administered Example No. orally orally 1 from 1.0 7 from 3.1) J from 3.0

The following nonlimitative examples more particularly describe the present invention:

EXAMPLE 1 11,0,0 H cooc, H, l I mi,

After heating a nitrobenzylideneacetozicetic acid ethyl ester, 1 L3 g of cyanoucetic acid ethyl ester and 2 ml of piperidine in 100 ml of ethanol for 4 hours, 2-amino-6-methyl-4-(3'- nitrophenyl)-4 H-pyrane-3,5dicarboxylic acid diethyl ester of melting point 161C (ethanol) was obtained. Yield 63% of theory.

EXAMPLE 2 H,c,ooc

l 1.1 g of l-diethylaminopropl-ine are added to a solution of 25.2 g of 2-chlorobenzylideneucetoucetic ucid ethyl ester in l()0 ml of toluene. After the first exothermic reaction. the mixture is boiled for 4 hours under reflux and the residue is distilled: Boiling point at 0.9 mm. Hg; 205C. 2-Diethylumino-3.o-dimethyl- 4( 2'-chlorophenyl )-4 H-pyrune-S-carboxylic acid ethyl ester. Yield 76% of theory.

EXAMPLE 3 CH H,C, 00 l H,c Meg-1,),

A solution of l5.o g of ethylideneacetoacetic acid ethyl ester and ll.l g of diethyluminoprop-l-ine is heated for 4 hours after the first vigorous reaction. The mixture is concentrated and the residue is distilled; Boiling point at (1.6 mm. Hg: ll'll26C. 2' Dicthylamino-fi.4,6-trimethyl4 H-pyrune-icurhoxylic acid ethyl ester. Yield 66 of theory.

solution of 26.3 g of 3'-- nitrobenzylideneucetoacetic acid methyl ester, ll.3 g of cyunoacetic acid ethyl ester and 2 ml of piperidine in ml of ethanol for 4 hours. 2-amino-6-methyl-4- (3'-nitrophenyl)-4 H-pyrzine-3.S-dicarboxylic acid 3- ethyl ester-S-methyl ester of melting point l34C was obtained. Yield 67% of theory.

EXAMPLE 5 CF, n,c,ooc H we idem,

A solution of 28.6 g of 2'-trit'luoromethylben zylideneaeetoacetic acid ethyl ester and 11.1 g of ldiethylaminoprop-l-ine in 200 m] of toluene is boiled for 4 hours under reflux after the first vigorous reaction. The mixture is concentrated and the residue is distilled: Boiling poing at 0.1 mm. Hg: I39- i46C. 2- Diethylamino-b 3,6-dimethyl-4-( 2 '-trifluoromethylphenyll-4 H-pyraneicurhoxylic acid ethyl ester. Yield 59% of theory.

EXAMPLE 6 A solution of 23.2 g of 2'-methylhenzylideneacetoacetic acid ethyl ester and l l.] g of l-diethylaminopropl-ine in ml of toluene is boiled for 4 hours under reflux after the first vigorous reaction. The mixture is concentrated and the residue distilled: Boiling point at 0.4 mm. Hg: l63-l74C. 2-Diethylamino-3,6- dimethyl-4-(2'-methylphenyl)-4 H-pyrane-S- earhoxylic acid ethyl ester.

EXAMPLE7 (11,0),scooc After heating ti solution of 27.7 g of 3' nitroheniylidencucetoucetic acid isopropyl ester. ll.3 g of cyunoucctic acid ethyl ester and 2 ml of piperidine in lt)() ml ol'ethanol for 4 ll) hours, 2-amino-6-methyl- 4-(3'-nitrophenyl)-4 H-pyrane-3.S-dicurhoxylic acid J-ethyl ester-S-isopropyl ester of melting point 135C (ethanol) was obtained. Yield 46% of theory.

EXAMPLE 8 H it,c,ooc ct-t,

5 (CIH, l

A solution of 21.8 g oi benzylideneacetoacetic acid ethyl ester and ll.l g of l-diethylaminoprop-l-ine in I50 ml of toluene is boiled for 4 hours under reflux after the first vigorous reaction. The mixture is concentrated and the residue is distilled: Boiling point at 0.2 mm. Hg: l42l55C. 2-Diethylamino-3.6-dimethyl-4- phenyl-4H-pyrane-S-carboxylic acid ethyl ester. Yield 62% oftheory.

EXAMPLE 9 H;C0C OOC H,

3 C NH;

On heating a solution of 23.3 gof3'-nitrobenzylidene aeetylacetone. ll.3 g of cyanoacetic acid ethyl ester and 2 ml of piperidine in 100 ml of ethanol for 4 hours, Z-aminofiacetyl-(i-methyl-4-( 3'-nitrophenyl )-4 H-pyrane-3-carhoxylic acid ethyl ester of melting point l8lC (ethanol) was obtained. Yield I?! of theory.

EXAMPLE l() OCH,

H ",C.0OC

l 11,0 c s):

A solution of 24.8 g of 2'-methoxybenzylidcneacetoacctic acid ethyl ester and ll.l g of ldiethylaminopropl -ine in l5() ml of toluene was boiled for 4 hours under reflux after the first vigorous reaction. The mixture is concentrated and the residue is distilled: Boiling point at 0.3 mm. Hg: l64-l68C. 2- Dieth lamino-3.6-dimethyl-4-l 2'-methoxyphenyl l-4H- yrane-5-carhoxylic acid ethyl ester. Yield 64% ofthe EXAMPLE ll Cl H,COOC I 2 H, NH.

On heating a solution of 28.4 g of 3'-nitro-6'- chlorobenzylideneacetoacetic acid methyl ester. 1 l.4 g of cyanoacetic acid ethyl ester and 2 ml of piperidine in l()() ml of ethanol for 4 hours. 2-amino-6-methyl-4- (3 '-nitro-6'-chlorophenyl )-4 H-pyrane-3.S- dicarboxylic acid 3-ethyl ester-S-methyl ester of melting point 159C was obtained. Yield 42% of theory.

EXAMPLE l2 3,6 N(CIHS)I A solution of 2L0 g of 2'-furfurylideneacetoacetic acid ethyl ester and l 1.1 g of l-diethylaminoprop-l-ine in ISO ml of toluene was boiled for 4 hours under reflux after the first vigorous reaction. The mixture is concentrated and the residue is distilled: Boiling point at 0.8 mm. Hg: l59l67C. 2-Diethylamino-3,6-dimethyl-4- (2'-furyl)-4 H-pyrane-S-carboxylic acid ethyl ester.

EXAMPLE l3 EXAMPLE 14 H5C20OC cs H36 0 N(C2H5)2 l 1.] g of l-diethylaminoprop-l-ine are added to a solution of 22.4 g of (2-thenylidene)-acetoacetic acid ethyl ester in lUU ml of toluene. After the first exothermic reaction. the mixture is boiled for 4 hours under reflux and the residue is distilled: Boiling point at 2 mm. Hg: l84l89C. 2-Diethylamino-3.6-dimethyl-4- (2'-thenyl)-4 H-pyrane-S-carhoxylic acid ethyl ester. Yield: 59'?! of theory.

EXAMPLE l5 a c ooc I H3 I [.1 g of l-diethylaminoprop- 1 -inc are added to a solution of 24.3 g of 2-cyanobenzylidencacetoacetic acid ethyl ester in l()(] ml of toluene. After the first exothermic reactionjthe mixture is boiled for 4 hours under reflux and the residue is distilled: Boiling point at 2 mm. Hg; l88l92C. Z-Diethylamino 3,6-dimethyl-4- [2 cyanophenyl)4 H-pyranefi-carboxylic acid ethyl ester. Yield 46% of theory.

EXAMPLE l6 cooc 1t H n c ooc l CH3 3 z fiz wherein R and R are each hydrogen;

R is COOR' wherein R is lower alkyl; lower alkenyl; or lower alkynyl; R is phenyl unsubstituted or substituted by 1, 2 of 3 of the same or different substituents selected from the group consisting of lower alkyl. lower alkoxy. halogen. nitro, cyano. trifluoro methyl, carbdower alkoxy) and SO,, lower alkyl wherein n is 0. l or 2. or naphthyl; R is OR" wherein R" is lower alkyl, lower alkenyl. lower alkynyl. cycloalkyl of 3 to 7 carbon atoms. or lower alkyl interrupted by 1 oxygen atom; and

R' is lower alkyl.

2. A compound according to claim I wherein R is COOR' wherein R' is alkyl of l to 5 carbon atoms. alkenyl of 2 to 5 carbon atoms or alkynyl of 2 to 5 carbon atoms;

R is phenyl unsubstituted or substituted or substituted by l or 2 ofthe same or different substituents selected from the group consisting of alkyl of l to 4 carbon atoms. alkoxy of l to 4 carbon atoms. halogen. nitro, cyano, trifluoromethyl. carbalkoxy of l to 4 carbon atoms in the alkoxy moiety and -SO,, alkyl wherein the alkyl moiety is of l to 4 carbon atoms and n is (l or 2, or naphthyl R is OR" wherein R" is alkyl l to 4 carbon atoms. alkenyl of 2 to 5 carbon atoms. alkynyl or 2 to 5 carbon atoms. cycloalkyl of 3 to 5 carbon atoms. or alkyl of l to 5 carbon atoms interruptedby l oxygen.

3. A compound according to claim I wherein R is COOR' wherein R is methyl. ethyl or allyl'. R is phenyl unsubstituted or substituted by nitro. cyano. trifluoromethyl. chloro. methyl. carbethoxy, l to 3 mcthoxy moieties. nitro and methoxy. nitro and trifluoromethyl, nitro and thiomcthyl. or nitro and chloro, or

R is naphthyl;

R is OR" wherein R" is methyl. ethyl, propyl. allyl or cyclohexyl; and

R" is methyl or ethyl.

4. A compound according to claim I wherein R is carbomethoxy. or carbethoxy;

R is phenyl, unsubstituted or substituted by nitro. chloro. trifluoromethyl. methyl methoxy. cyano. carbethoxy or nitro and chloro; or

R is naphthyl;

R is methoxy, cthoxy. or propoxy; and

R is methyl.

5. The compound according to claim I which is 2- amino-6-methyl-4-t 2-nitrophenyl )-4 H-pyrane-3,5 dicarboxylic acid diethyl ester.

6. The compound according to claim 1 which is 2- amino-6-methyl-4-(2' nitrophenyl)-4 H-pyrane-3 S- dicarboxylic acid 3-ethyl ester S-methyl ester.

7. The compound according to claim 1 which is 2- amino-6-ethyl-4-( 3 '-nitrophenyl )-4 H-pyrane-3,5- dicarboxylic acid diethyl ester.

8. The compound according to claim 1 which is 2- amino-6-methyl-4-(3-nitro-6'-methoxyphenyl)-4 H- pyrane3.5-dicarboxylic acid diethyl ester.

9. The compound according to claim 1 which is 2- amino-6methyl-4-(2'-trifluoromethyl-4'-nitrophenyl)- 4 H-pyrane'3,S-dicarboxylic acid 3-ethyl cster5- methyl ester.

10. The compound according to claim 1 which is 2- amino-o-methyl-4-(3-nitro-6'- methylmercaptophenyl]-3.5 dicarboxylic methyl ester.

11. The compound according to claim I which is 2- amino-6-methyl-4t3'-cyanophenyl)-4 H-pyrane-3.5- dicarboxylic acid 3 allyl ester-5 ethyl ester.

l2. The compound according to claim 1 which is 2- amino-6-methyl4( 3'-nitrophenyl)-4 H-pyrane-Bjdicarboxylic acid 3-ethyl ester-S-cyclohexyl ester.

13. The compound according to claim 1 which is acid din,c,ooc H Z S l Ol 14. The compound according to claim I which is H,C0 ooc s, l l H,C H,

15. The compound according to claim 1 which is 16. The compound according to claim I which is m H,cooc

COOCIH, 

1. A COMPOUND OF THE FORMULA
 2. A compound according to claim 1 wherein R3 is -COOR'' wherein R'' is alkyl of 1 to 5 carbon atoms, alkenyl of 2 to 5 carbon atoms or alkynyl of 2 to 5 carbon atoms; R4 is phenyl unsubstituted or substituted or substituted by 1 or 2 of the same or different substituents selected from the group consisting of alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, halogen, nitro, cyano, trifluoromethyl, carbalkoxy of 1 to 4 carbon atoms in the alkoxy moiety and -SOn alkyl wherein the alkyl moiety is of 1 to 4 carbon atoms and n is 0 or 2, or naphthyl R5 is -OR'''' wherein R'''' is alkyl 1 to 4 carbon atoms, alkenyl of 2 to 5 carbon atoms, alkynyl or 2 to 5 carbon atoms, cycloalkyl of 3 to 5 carbon atoms, or alkyl of 1 to 5 carbon atoms interrupted by 1 oxygen.
 3. A compound according to claim 1 wherein R3 is -COOR'' wherein R'' is methyl, ethyl or allyl; R4 is phenyl unsubstituted or substituted by nitro, cyano, trifluoromethyl, chloro, methyl, carbethoxy, 1 to 3 methoxy moieties, nitro and methoxy, nitro and trifluoromethyl, nitro and thiomethyl, or nitro and chloro, or R4 is naphthyl; R5 is -OR'''' wherein R'''' is methyl, ethyl, propyl, allyl or cyclohexyl; and R6 is methyl or ethyl.
 4. A compound according to claim 1 wherein R3 is carbomethoxy, or carbethoxy; R4 is phenyl, unsubstituted or substituted by nitro, chloro, trifluoromethyl, methyl, methoxy, cyano, carbethoxy or nitro and chloro; or R4 is naphthyl; R5 is methoxy, ethoxy, or propoxy; and R6 is methyl.
 5. The compound according to claim 1 which is 2-amino-6-methyl-4-(2''-nitrophenyl)-4 H-pyrane-3,5-dicarboxylic acid diethyl ester.
 6. The compound according to claim 1 which is 2-amino-6-methyl-4-(2''-nitrophenyl)-4 H-pyrane-3,5-dicarboxylic acid 3-ethyl ester 5-methyl ester.
 7. The compound according to claim 1 which is 2-amino-6-ethyl-4-(3''-nitrophenyl)-4 H-pyrane-3,5-dicarboxylic acid diethyl ester.
 8. The compound according to claim 1 which is 2-amino-6-methyl-4-(3''-nitro-6''-methoxyphenyl)-4 H-pyrane3,5-dicarboxylic acid diethyl ester.
 9. The compound according to claim 1 which is 2-amino-6-methyl-4-(2''-trifluoromethyl-4''-nitrophenyl)-4 H-pyrane-3,5-dicarboxylic acid 3-ethyl ester-5-methyl ester.
 10. The compound according to claim 1 which is 2-amino-6-methyl-4-(3''-nitro-6''-methylmercaptophenyl)-3,5-dicarboxylic acid dimethyl ester.
 11. The compound according to claim 1 which is 2-amino-6-methyl-4(3''-cyanophenyl)-4 H-pyrane-3,5-dicarboxylic acid 3-allyl ester-5 ethyl ester.
 12. The compound according to claim 1 which is 2-amino-6-methyl-4-(3''-nitrophenyl)-4 H-pyrane-3,5-dicarboxylic acid 3-ethyl ester-5-cyclohexyl ester.
 13. The compound according to claim 1 which is
 14. The compound according to claim 1 which is
 15. The compound according to claim 1 which is
 16. The compound according to claim 1 which is 